Intratumoral Alpha-Emitter Radiation in Combination with Immune Checkpoint Regulators

Abstract

A substance which regulates immune-checkpoints for use as a medicament for treatment of a tumor of a patient wherein the administration pattern of the medicament comprises administering a therapeutically effective amount of the substance to the tumor, in one or more sessions, and implanting seeds (204) carrying radium-224 in the tumor for intra-tumoral alpha-emitter radiotherapy less than two weeks from administering the substance.

1 . A substance which regulates immune-checkpoints for use as a medicament for treatment of a tumor of a patient wherein the administration pattern of the medicament comprises administering a therapeutically effective amount of the substance to the tumor, in one or more sessions, and implanting seeds carrying radium-224 in the tumor for intra-tumoral alpha-emitter radiotherapy less than two weeks from administering the substance. 
     
     
         2 . The substance as in  claim 1 , wherein the administration pattern of the medicament comprises beginning the administering the substance within less than five days from implanting of the seeds. 
     
     
         3 . The substance as in  claim 1 , wherein the administration pattern of the medicament comprises beginning the administering of the substance at least 12 hours after the implanting of the seeds. 
     
     
         4 . The substance as in  claim 1 , wherein the administration pattern of the medicament comprises beginning the administering of the substance at least 72 hours after the implanting of the seeds. 
     
     
         5 . The substance as in  claim 1 , wherein the administration pattern of the medicament comprises beginning the administering of the substance at least 12 hours before the implanting of the seeds. 
     
     
         6 . The substance as in  claim 1 , wherein the administration pattern of the medicament comprises beginning the administering of the substance at least 72 hours before the implanting of the seeds. 
     
     
         7 . The substance as in  claim 1 , wherein the substance comprises an antiangiogenic agent. 
     
     
         8 . The substance as claimed in  claim 1 , wherein the substance comprises a checkpoint inhibitor. 
     
     
         9 . The substance as claimed in  claim 1 , wherein the substance comprises small molecule inhibitors. 
     
     
         10 . The substance as claimed in  claim 1 , wherein the substance comprises Nivolumab, pembrolizumab, cemiplimab, toripalimab, or sintilimab. 
     
     
         11 . The substance as claimed in  claim 1 , wherein the substance comprises Atezolizumab, avelumab, or durvalumab. 
     
     
         12 . The substance as claimed in  claim 1 , wherein the substance comprises Ipilimumab. 
     
     
         13 . The substance as claimed in  claim 1 , wherein the substance comprises Relatlimab. 
     
     
         14 . The substance as claimed in  claim 1 , wherein the substance comprises LY3321367. 
     
     
         15 . The substance as claimed in  claim 1 , wherein the substance comprises Tiragolumab. 
     
     
         16 . The substance as claimed in  claim 1 , wherein the substance comprises Epacadostat. 
     
     
         17 . The substance as claimed in  claim 1 , wherein the substance comprises Enoblituzumab. 
     
     
         18 . The substance as claimed in  claim 1 , wherein the substance comprises HLX23 or ORIC-533. 
     
     
         19 . The substance as claimed in  claim 1 , wherein the substance comprises Monalizumab. 
     
     
         20 . The substance as claimed in  claim 1 , wherein the substance comprises pexidartinib or Lacnotuzumab. 
     
     
         21 . The substance as claimed in  claim 1 , wherein the substance comprises Pepinemab. 
     
     
         22 . The substance as claimed in  claim 1 , wherein the substance comprises Enapotamab. 
     
     
         23 . The substance as claimed in  claim 1 , wherein the substance comprises tavolimab or cudarolimab. 
     
     
         24 . The substance as claimed in  claim 1 , wherein the substance comprises Vopratelimab, sotigalimab or Elotuzumab. 
     
     
         25 . The substance as in  claim 1 , wherein the seeds comprise:
 a support having a length of at least 1 millimeter; and   radium-224 atoms coupled to the support such that not more than 20% of the radium-224 atoms leave the support into the tumor in 24 hours, without decay, when the seed is implanted in the tumor, but upon decay, at least 5% of daughter radionuclides of the radium-224 atoms leave the support upon decay.   
     
     
         26 . A method of treating a patient with a tumor, comprising:
 treating the tumor with intra-tumoral alpha-emitter radiotherapy; and   administering, to the patient, a substance which regulates immune checkpoints within two weeks of beginning the treating of the tumor with intra-tumoral alpha-emitter radiotherapy.   
     
     
         27 . The method of  claim 26 , wherein administering the substance comprises administering an immune checkpoint inhibitor. 
     
     
         28 . The method of  claim 26 , wherein administering the substance comprises administering an immune checkpoint bi-specific antibody. 
     
     
         29 . The method of  claim 26 , wherein administering the substance comprises administering a molecule that internalizes immune checkpoints. 
     
     
         30 . The method of  claim 26 , wherein administering the substance comprises administering a LAG3 checkpoint inhibitor. 
     
     
         31 . The method of  claim 26 , wherein administering the substance comprises administering a PD-1 checkpoint inhibitor. 
     
     
         32 . The method of  claim 26 , wherein administering the substance comprises administering a PDL-1 checkpoint inhibitor. 
     
     
         33 . The method of  claim 26 , wherein administering the substance comprises administering a CTLA4 checkpoint inhibitor. 
     
     
         34 . The method of  claim 26 , wherein administering the substance comprises administering a small molecule inhibitor. 
     
     
         35 . The method of  claim 26 , wherein administering the substance comprises administering a Costimulatory molecule. 
     
     
         36 . The method of  claim 26 , wherein administering the substance comprises administering nivolumab or pembrolizumab. 
     
     
         37 . The method of  claim 26 , wherein administering the substance comprises administering atezolizumab, avelumab or durvalumab. 
     
     
         38 . The method of  claim 26 , wherein administering the substance comprises administering ipilimumab or Tremelimumab. 
     
     
         39 . The method of  claim 26 , wherein administering the substance comprises administering Relatlimab. 
     
     
         40 . The method of  claim 26 , wherein administering the substance comprises administering tebotelimab. 
     
     
         41 . The method of  claim 26 , wherein administering the substance comprises administering TSR-022. 
     
     
         42 . The method of  claim 26 , wherein administering the substance comprises administering Etigilimab or Tiragolumab. 
     
     
         43 . The method of  claim 26 , wherein administering the substance comprises administering Enoblituzumab. 
     
     
         44 . The method of  claim 26 , wherein administering the substance comprises administering pomalidomide. 
     
     
         45 . The method of  claim 26 , wherein administering the substance comprises administering berzosertib. 
     
     
         46 . The method of  claim 26 , wherein administering the substance comprises administering celecoxib. 
     
     
         47 . The method of  claim 26 , wherein administering the substance comprises administering Vemurafenib. 
     
     
         48 . The method of  claim 26 , wherein administering the substance comprises administering vorinostat. 
     
     
         49 . The method of  claim 26 , wherein administering the substance comprises administering sorafenib or sunitinib. 
     
     
         50 . The method of  claim 26 , wherein administering the substance comprises administering tavolimab. 
     
     
         51 . The method of  claim 26 , wherein administering the substance comprises administering Elotuzumab. 
     
     
         52 . The method of  claim 26 , wherein administering the substance comprises administering the substance at least 72 hours after beginning the treating of the tumor with intra-tumoral alpha-emitter radiotherapy. 
     
     
         53 . The method of  claim 26 , wherein administering the substance comprises administering the substance less than two weeks after beginning the treating of the tumor with intra-tumoral alpha-emitter radiotherapy. 
     
     
         54 . The method of  claim 26 , wherein administering the substance comprises administering the substance less than 144 hours after beginning the treating of the tumor with intra-tumoral alpha-emitter radiotherapy. 
     
     
         55 . The method of  claim 26 , wherein administering the substance comprises administering an immune checkpoint blockade. 
     
     
         56 . A kit for treatment of a patient, comprising:
 at least one source for being at least partially introduced into a body of a subject, having alpha-emitting atoms mounted thereon;   at least one immune checkpoint regulator; and   a package containing the at least one source and the at least one immune checkpoint regulator.   
     
     
         57 . An alpha-emitting device designed for use in alpha-emitter radiotherapy treatment of a tumor of a patient wherein the alpha-emitter radiotherapy treatment pattern comprises treating the tumor with the alpha-emitter device followed by administering a therapeutically effective amount of an immune checkpoint regulator, in one or more sessions, less than six weeks after beginning the alpha-emitter radiotherapy. 
     
     
         58 . The alpha-emitting device of  claim 57 , wherein the alpha-emitter radiotherapy treatment pattern comprises treating the tumor with the alpha-emitter device followed by administering a therapeutically effective amount of an immune checkpoint regulator, in one or more sessions, less than two weeks after beginning the alpha-emitter radiotherapy. 
     
     
         59 . An alpha-emitting device designed for use in alpha-emitter radiotherapy treatment of a population having a tumor treated with a therapeutically effective amount of an immune checkpoint regulator, in one or more sessions, less than six weeks after beginning the alpha-emitter radiotherapy.